1. RELEVANCERELEVANCE Is the objective of the article on harm similar to your clinical dilemma? Yes, the article’s objective is similar to the clinical dilemma because both aim to identify the harmful effects of prolonged treatment with hydroxychloroquine for SLE patients, as stated in Page 1321, paragraph 2 C S L C I E N I A C R A I L O Will prolonged treatment with hydroxychloroquine cause harmful effects in SLE patients? HARM

2. VALIDITYGUIDESVALIDITYGUIDES Did investigator assemble clearly defined groups of patients similar in all important ways other than exposure? Yes. Besides the dose and duration of exposure, groups were defined as to similarities in age group, gender, nationality, disease, inclusion and exclusion criteria, stated in Pages 1321-1322, Patients and Methods, paragraphs 1 and 2 Were exposures and outcomes measured in the same ways in both groups (objective/blinded)? Yes, exposures and outcomes were measured similarly in groups who did and did not present with the outcome. Methods of measuring exposures (particularly the dose and duration), and outcomes (evidence of retinal pathology) were standardized in all patients of both groups as stated in Page 1322, Patients and Methods, paragraph 2, sentences 3 and 4 and paragraph 3, sentence 2

3. VALIDITYGUIDESVALIDITYGUIDES Was follow-up sufficiently long and complete? Yes. Follow up was sufficiently long and complete for all patients, with a mean of 8.7 years. Follow up consisted of ophthalmologic assessment and fluorescence angiography as stated in Page 1322, Patients and Methods, paragraph 3, sentence 1 and Results, paragraph 3, sentence 3 Do the results of the harm study fulfill some of the tests for causation? A. Is it clear that the exposure preceded the onset of the outcome? Yes. Before exposing the patients to a controlled dose and duration of hydroxychloroquine, a baseline ophthalmic examination was performed to confirm that there was no preexisting fundus pathology. Presence of retinopathy after the initiation of hydroxychloroquine as treatment proves that the exposure preceded the onset of the outcome as stated in Page 1325, Discussion, last paragraph

4. VALIDITYGUIDESVALIDITYGUIDES Is there a dose responsive relationship? None. Table 1 showed that there is no relationship between the duration of treatment and the development of HCQ-related retinopathy. In page 1322 under results, its states that there are no HCQ- related retinal toxicity noted in any of the longterm–treated 400 patients during the first 6 years. Also in Table 1, the overall incidence of HCQ-related retinopathy in the 400 patients who were treated with recommended dosages of the drug and had completed a mean of 8.7 years of follow-up at the time of the analysis was reduced to 0.5%. Therefore, long-term use of the drug at recommended dosage will not increase the risk of developing retinopathy. Table 1. Incidence of Irreversible Hydroxychloroquine-Related Retinopathy Among Patients Treated with Recommended Dosages of the Drug for >6 Years, Evaluated from 1985 to 1995 and 1985 to 2000 Variable1985–19951985–2000 No. of patients at risk 58400 Mean duration of treatment (yrs) 7.58.7 Cases of irreversible retinopathy 22 Incidence3.4%0.5%

5. VALIDITYGUIDESVALIDITYGUIDES Any positive evidence from a dechallenge-rechallenge study? This study is prospective continuation of a study done in 1996 at which there were 2 (3.4%) cases of irreversible HCQ-related maculopathy among 58 long term treated patients, occuring at 8 and 6.5 years of treatment, respectively. The current study extended the spectrum of patients and duration of treatment into 342 long-term–treated patients to year 2000. Also exhibited in Table 1, the Overall, the incidence of irreversible HCQ-related retinopathy in 400 patients who were treated with recommended dosages of the drug for >6 years was reduced to 0.5%. Is the association consistent across studies? Yes. Stated in the conclusion, in the cohort of subjects, the overall incidence of HCQ-induced retinal toxicity, even in those treated for >6 years, was <1%.

6. VALIDITYGUIDESVALIDITYGUIDES Does the association have biological plausibility? Yes. There is only 0.5% overall incidence of irreversible HCQ-related retinopathy for patients who were treated with recommended dosages of the drug for >6 years which substantiates the current guidelines of American Academy of Ophthalmology Task Force for screening for HCQ toxicity. Screening of such patients during the first 5 years of treatment can be at the frequency of regular ophthalmic examinations recommended by the American Academy of Ophthalmology Preferred Practice Pattern for the age of the patient, providing that no concomitant retinal, renal, or liver disease exists.

7. CLINICALIMPORTANCECLINICALIMPORTANCE How precise is the estimate of the treatment effect? (p1322, under Results; 1st column, 2nd paragraph) (p1322, under Results, 2nd column, 1st paragraph) The estimate of the treatment effect was precise. It was stated in the study that before the onset of the treatment, factors that will invalidate the result of the treatment effect was evaluated and identified. It was found that such factors were absent on the patients. The patients were also monitored by routine ophthalmologic examinations to assess their conditions. Complete follow-up was done to ensure the validity of the result. All of these contribute for the estimate of the treatment effect to be precise. What is the magnitude of the treatment (NNH) 1/0.005 = 200 for every 200 patients who will be receiving Hydroxychloroquine, there will be 1 patient who will develop retinopathy.

8. APPLICABILITYAPPLICABILITY Is our patient so different from those in the study that its result cannot apply? No, our patient is the same with the patients included in the study. The patients in the study comprise of both male and female and since our patient’s gender was not stated, this study can be applicable to both genders. 161 patients in the study had SLE and our patient manifests signs and symptoms of the same condition. The age of our patient (29 years old) falls within the range of the age of the patient in the study (between 18 and 83 years old). Therefore, having same characteristics of our patient with the patients in the study, the result can apply to our patient. (p1322, under Patients and Methods; 1st column, 2nd paragraph) What is our patient’s risk of benefit and harm from the exposure? Our patient will be treated from SLE but there is a risk of retinal toxicity that can develop upon exposure from hydroxychloroquine. (p1321; 1st column, 1st paragraph)

9. APPLICABILITYAPPLICABILITY What are our patient’s preferences, concerns, and expectations from the treatment? Our patient main concern to hydroxychloroquine will be the potential risk of common or serious adverse effects of the drug, particularly retinal damage. Because of the potential retinal toxicity, our patient prefers to take recommended dose ≤6.5mg/kg daily of hydroxychloroquine and continue safely for 6 years. However, he/she will undergo ophthalmologic examinations at least annually. It is expected from hydroxychloroquine that it will suppress his/her symptoms to an acceptable level, reduce the number of disease flares and reduce accrual of tissue damage over time. (p1323-1324, under Discussion; 2nd column, 1st paragraph) (p1324, under Discussion; 2nd column, 2nd paragraph) What alternative treatments are available? Since our patient has non-life-threatening disease, conservative therapies are applicable. Management will be directed to suppression of symptoms. Analgesics and antimalarials are the mainstays. Therefore alternative treatment for our patient would be NSAIDS and other antimalarials like quinacrine but not chloroquine. Since chloroquine is more retinotoxic than hydroxychloroquine due partly to the fact that cloroquine crosses the blood-retinal barrier, whereas hydroxychloroquine does not. However, there are issues regarding the use of NSAIDS. There is an increased risk of NSAID-induced aseptic meningitis, elevated serum transaminases, hypertension, and renal dysfunction. There is also an increase risk of myocardial infarction especially in COX-2 inhibitors. (p1321; 2nd column, 1st paragraph)